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GSK-3 is a master regulator of neural progenitor homeostasis

Nature Neuroscience volume 12, pages 1390–1397 (2009)Cite this article

Abstract

The development of the brain requires the exquisite coordination of progenitor proliferation and differentiation to achieve complex circuit assembly. It has been suggested that glycogen synthase kinase 3 (GSK-3) acts as an integrating molecule for multiple proliferation and differentiation signals because of its essential role in the RTK, Wnt and Shh signaling pathways. We created conditional mutations that deleted both the α and β forms of GSK-3 in mouse neural progenitors. GSK-3 deletion resulted in massive hyperproliferation of neural progenitors along the entire neuraxis. Generation of both intermediate neural progenitors and postmitotic neurons was markedly suppressed. These effects were associated with the dysregulation of β-catenin, Sonic Hedgehog, Notch and fibroblast growth factor signaling. Our results indicate that GSK-3 signaling is an essential mediator of homeostatic controls that regulate neural progenitors during mammalian brain development.

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Figure 1: GSK-3 deletion leads to a massive increase in neural progenitor proliferation.
Figure 2: Conversion of radial progenitors to INPs is suppressed by GSK-3 deletion.
Figure 3: GSK-3 deletion in progenitors strongly inhibits neurogenesis.
Figure 4: Neurogenesis is inhibited through E15.5.
Figure 5: Dysregulation of β-catenin and Shh signaling components as a result of GSK-3 deletion.
Figure 6: Changes in Notch signaling components and contributions of β-catenin and Notch signaling to GSK-3 deletion effects.
Figure 7: GSK-3 mediates FGF-PI3K signaling to regulate c-Myc in neural progenitors.

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References

  1. Doble, B.W. & Woodgett, J.R. GSK-3: tricks of the trade for a multi-tasking kinase. J. Cell Sci. 116, 1175–1186 (2003).

    Article  CAS  Google Scholar 

  2. Kockeritz, L., Doble, B., Patel, S. & Woodgett, J.R. Glycogen synthase kinase-3: an overview of an over-achieving protein kinase. Curr. Drug Targets 7, 1377–1388 (2006).

    Article  CAS  Google Scholar 

  3. Beaulieu, J.M., Gainetdinov, R.R. & Caron, M.G. The Akt–GSK-3 signaling cascade in the actions of dopamine. Trends Pharmacol. Sci. 28, 166–172 (2007).

    Article  CAS  Google Scholar 

  4. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P. & Brivanlou, A.H. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat. Med. 10, 55–63 (2004).

    Article  CAS  Google Scholar 

  5. Ying, Q.L. et al. The ground state of embryonic stem cell self-renewal. Nature 453, 519–523 (2008).

    Article  CAS  Google Scholar 

  6. Bone, H.K. et al. Involvement of GSK-3 in regulation of murine embryonic stem cell self-renewal revealed by a series of bisindolylmaleimides. Chem. Biol. 16, 15–27 (2009).

    Article  CAS  Google Scholar 

  7. Mao, Y. et al. Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling. Cell 136, 1017–1031 (2009).

    Article  CAS  Google Scholar 

  8. Corbin, J.G. et al. Regulation of neural progenitor cell development in the nervous system. J. Neurochem. 106, 2272–2287 (2008).

    Article  CAS  Google Scholar 

  9. Shimizu, T. et al. Stabilized beta-catenin functions through TCF/LEF proteins and the Notch/RBP-Jkappa complex to promote proliferation and suppress differentiation of neural precursor cells. Mol. Cell. Biol. 28, 7427–7441 (2008).

    Article  CAS  Google Scholar 

  10. Knoepfler, P.S. & Kenney, A.M. Neural precursor cycling at sonic speed: N-Myc pedals, GSK-3 brakes. Cell Cycle 5, 47–52 (2006).

    Article  CAS  Google Scholar 

  11. Bechard, M. & Dalton, S. Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal. Mol. Cell. Biol. 29, 2092–2104 (2009).

    Article  CAS  Google Scholar 

  12. Doble, B.W. & Woodgett, J.R. Exploring pluripotency with chemical genetics. Cell Stem Cell 4, 98–100 (2009).

    Article  CAS  Google Scholar 

  13. Otto, T. et al. Stabilization of N-Myc is a critical function of Aurora A in human neuroblastoma. Cancer Cell 15, 67–78 (2009).

    Article  CAS  Google Scholar 

  14. Jia, J. et al. Shaggy/GSK3 antagonizes Hedgehog signaling by regulating Cubitus interruptus. Nature 416, 548–552 (2002).

    Article  CAS  Google Scholar 

  15. Espinosa, L., Ingles-Esteve, J., Aguilera, C. & Bigas, A. Phosphorylation by glycogen synthase kinase 3 beta downregulates Notch activity, a link for Notch and Wnt pathways. J. Biol. Chem. 278, 32227–32235 (2003).

    Article  CAS  Google Scholar 

  16. Uemura, K. et al. GSK3beta activity modifies the localization and function of presenilin 1. J. Biol. Chem. 282, 15823–15832 (2007).

    Article  CAS  Google Scholar 

  17. Jin, Y.H., Kim, H., Oh, M., Ki, H. & Kim, K. Regulation of Notch1/NICD and Hes1 expressions by GSK-3alpha/beta. Mol. Cells 27, 15–19 (2009).

    Article  CAS  Google Scholar 

  18. Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat. Genet. 23, 99–103 (1999).

    Article  CAS  Google Scholar 

  19. Yokota, Y. et al. The adenomatous polyposis coli protein is an essential regulator of radial glial polarity and construction of the cerebral cortex. Neuron 61, 42–56 (2009).

    Article  CAS  Google Scholar 

  20. MacAulay, K. et al. Glycogen synthase kinase 3alpha–specific regulation of murine hepatic glycogen metabolism. Cell Metab. 6, 329–337 (2007).

    Article  CAS  Google Scholar 

  21. Patel, S. et al. Tissue-specific role of glycogen synthase kinase 3beta in glucose homeostasis and insulin action. Mol. Cell. Biol. 28, 6314–6328 (2008).

    Article  CAS  Google Scholar 

  22. Kim, W.Y. et al. Essential roles for GSK-3s and GSK-3–primed substrates in neurotrophin-induced and hippocampal axon growth. Neuron 52, 981–996 (2006).

    Article  CAS  Google Scholar 

  23. Sessa, A., Mao, C.A., Hadjantonakis, A.K., Klein, W.H. & Broccoli, V. Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron 60, 56–69 (2008).

    Article  CAS  Google Scholar 

  24. Ding, Q. et al. Diminished Sonic hedgehog signaling and lack of floor plate differentiation in Gli2 mutant mice. Development 125, 2533–2543 (1998).

    CAS  PubMed  Google Scholar 

  25. Chenn, A. & Walsh, C.A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

    Article  CAS  Google Scholar 

  26. Woodhead, G.J., Mutch, C.A., Olson, E.C. & Chenn, A. Cell-autonomous beta-catenin signaling regulates cortical precursor proliferation. J. Neurosci. 26, 12620–12630 (2006).

    Article  CAS  Google Scholar 

  27. Chen, S. et al. Wnt-1 signaling inhibits apoptosis by activating beta-catenin/T cell factor–mediated transcription. J. Cell Biol. 152, 87–96 (2001).

    Article  CAS  Google Scholar 

  28. Götz, M. & Huttner, W.B. The cell biology of neurogenesis. Nat. Rev. Mol. Cell Biol. 6, 777–788 (2005).

    Article  Google Scholar 

  29. Dehay, C. & Kennedy, H. Cell-cycle control and cortical development. Nat. Rev. Neurosci. 8, 438–450 (2007).

    Article  CAS  Google Scholar 

  30. Zechner, D. et al. Beta-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Dev. Biol. 258, 406–418 (2003).

    Article  CAS  Google Scholar 

  31. Machon, O. et al. A dynamic gradient of Wnt signaling controls initiation of neurogenesis in the mammalian cortex and cellular specification in the hippocampus. Dev. Biol. 311, 223–237 (2007).

    Article  CAS  Google Scholar 

  32. Gulacsi, A.A. & Anderson, S.A. Beta-catenin–mediated Wnt signaling regulates neurogenesis in the ventral telencephalon. Nat. Neurosci. 11, 1383–1391 (2008).

    Article  CAS  Google Scholar 

  33. Yoon, K. & Gaiano, N. Notch signaling in the mammalian central nervous system: insights from mouse mutants. Nat. Neurosci. 8, 709–715 (2005).

    Article  CAS  Google Scholar 

  34. Mizutani, K., Yoon, K., Dang, L., Tokunaga, A. & Gaiano, N. Differential Notch signaling distinguishes neural stem cells from intermediate progenitors. Nature 449, 351–355 (2007).

    Article  CAS  Google Scholar 

  35. Shimojo, H., Ohtsuka, T. & Kageyama, R. Oscillations in notch signaling regulate maintenance of neural progenitors. Neuron 58, 52–64 (2008).

    Article  CAS  Google Scholar 

  36. He, T.C. et al. Identification of c-MYC as a target of the APC pathway. Science 281, 1509–1512 (1998).

    Article  CAS  Google Scholar 

  37. Calvisi, D.F., Ladu, S., Factor, V.M. & Thorgeirsson, S.S. Activation of beta-catenin provides proliferative and invasive advantages in c-myc/TGF-alpha hepatocarcinogenesis promoted by phenobarbital. Carcinogenesis 25, 901–908 (2004).

    Article  CAS  Google Scholar 

  38. Eilers, M. & Eisenman, R.N. Myc's broad reach. Genes Dev. 22, 2755–2766 (2008).

    Article  CAS  Google Scholar 

  39. Cappello, S. et al. The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface. Nat. Neurosci. 9, 1099–1107 (2006).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank F. Polleux, L. Pevny and E. Anton for valuable advice and comments on the manuscript. We are also grateful to L. Goins and A. McKell for animal care and M. Aita for technical support. This research was supported by grants from the US National Institutes of Health (NS050968 to W.D.S. and NS045892, which supports the Confocal and Multiphoton Imaging and Expression Localization Cores of University of North Carolina Neuroscience Center) and Canadian Institutes of Health Research (MOP 74711 to J.R.W.).

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Authors and Affiliations

  1. Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina, USA

    Woo-Yang Kim, Xinshuo Wang, Yaohong Wu & William D Snider

  2. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, Canada

    Bradley W Doble

  3. Mount Sinai Hospital and Department of Medical Biophysics, Samuel Lunenfeld Research Institute, University of Toronto, Toronto, Ontario, Canada

    Satish Patel & James R Woodgett

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  1. Woo-Yang Kim
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  2. Xinshuo Wang
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  4. Bradley W Doble
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Contributions

W.-Y.K. designed and conducted most of the experiments, analyzed the data, and co-wrote the paper. X.W. contributed to the in vitro experiments and ideas. Y.W. conducted western blotting and contributed technical assistance. B.W.D. and S.P. generated the GSK-3 mutant lines. J.R.W. contributed to experimental design, provided intellectual guidance and co-wrote the paper. W.D.S. supervised the work, contributed to the experimental design, provided intellectual guidance and co-wrote the paper.

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Correspondence to William D Snider.

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Kim, WY., Wang, X., Wu, Y. et al. GSK-3 is a master regulator of neural progenitor homeostasis. Nat Neurosci 12, 1390–1397 (2009). https://doi.org/10.1038/nn.2408

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